Uptake and Mutagenicity of Moderately Soluble Hexavalent Chromium

描述(申请人提供)：六价铬(六价铬)是一种已知的人类肺癌致癌物质。全世界有数以百万计的工人接触到铬(VI)。最新的范例提出，适度水溶性的铬酸盐化合物比不溶于水或水溶性的铬酸盐化合物更具致癌性；然而，为什么会这样，目前还不清楚。关于铬如何损伤DNA并导致DNA突变的大部分数据要么来自不溶的铬酸盐，要么来自水溶性的铬酸盐，而不是来自可能是最具致癌性的中等可溶性的铬酸盐。中度可溶的铬酸盐为铬酸锌、铬酸锶和铬酸钙。关于这些适度溶解的铬酸盐的活性，缺乏几个关键的信息。这些化合物对人肺上皮细胞的致突变性研究尚未进行，而人肺上皮细胞是肿瘤形成的靶细胞。这些化合物引起的突变类型尚未在任何细胞系中得到表征。这些铬酸盐的相对致突变性尚不清楚。这些化合物在细胞外溶解或以颗粒形式进入细胞的程度尚不清楚。锌、锶和钙反离子在铬酸盐毒性中的作用尚不清楚。目前建议的目标是解释(1)中等可溶的铬(VI)化合物如何进入细胞，以及(2)中等可溶的铬酸盐引起的突变是否与可溶和不可溶的铬酸盐引起的突变不同。这项提议的第一个目的是应用电感耦合等离子体质谱、激光扫描共聚焦显微镜、透射电子显微镜和扫描电子显微镜等技术来确定中等可溶性的铬酸盐如何进入细胞。这项建议的第二个目的是测量和表征中等可溶性铬酸盐引起的人肺上皮细胞次黄嘌呤(鸟嘌呤)磷酸核糖基转移酶(HPRT)基因突变，并将突变频率和同一性与可溶性和不溶性铬酸盐引起的突变进行比较。这些实验的数据将确定这些铬酸盐的相对致突变性，并将使人们深入了解作用机制，即反离子的参与和导致突变的可能DNA损伤。该提案的数据将提供彻底的人类风险评估所需的行动模式信息。这项工作的目的是确定铬(VI)是如何致癌的。这项建议的目的是解释(1)中等可溶的铬(VI)化合物如何进入细胞，以及(2)中等可溶的铬酸盐引起的突变是否与致癌性较低的可溶和不可溶的铬酸盐引起的突变不同。了解这些铬酸盐的作用模式将为人类风险评估提供基础。

DESCRIPTION (provided by applicant): Hexavalent chromium (Cr(VI)) is a known human lung carcinogen. Millions of workers are exposed to Cr(VI) worldwide. The most recent paradigm proposes that the chromate compounds that are moderately water-soluble are more carcinogenic than the chromates that are either insoluble or water-soluble; however, it is not understood why this is so. Most of the data on how chromium damages DNA and causes DNA mutations has come from either the insoluble chromates or the water soluble chromates, not from the moderately soluble chromates that may be the most carcinogenic. The moderately soluble chromates are zinc chromate, strontium chromate and calcium chromate. Several crucial pieces of information are lacking regarding the activity of these moderately soluble chromates. No mutagenicity studies have been carried out with these compounds in human lung epithelial cells, which are the target cells for tumor formation. The types of mutations that these compounds cause have not been characterized in any cell line. The relative mutagenic potency of these chromates is not known. The extent to which these compounds dissolve outside of cells or enter cells as particulates is not known. The involvement of the zinc, strontium and calcium counterions in chromate toxicity is not known. The goals of the current proposal are to explain (1) how the moderately soluble Cr(VI) compounds enter cells and (2) if the mutations caused by the moderately soluble chromates differ from those caused by the soluble and insoluble chromates. The first aim of this proposal will apply the techniques of inductively coupled plasma mass spectrometry, laser scanning confocal microscopy, transmission electron microscopy, and scanning electron microscopy to determine how the moderately soluble chromates enter cells. The second aim of this proposal will measure and characterize mutations at the hypoxanthine (guanine) phosphoribosyl transferase (hprt) locus caused by the moderately soluble chromates in human lung epithelial cells and will compare mutation frequency and identity with mutations caused by the soluble and insoluble chromates. Data from these experiments will determine the relative mutagenic potency of these chromates, and will give insight into mechanisms of action, i.e., involvement of counterion and possible DNA lesions responsible for the mutations. Data from this proposal will provide mode of action information that will be necessary for thorough human risk assessment. The purpose of this work is to determine how chromium(VI) causes cancer. The goals of this proposal are to explain (1) how the moderately soluble chromium(VI) compounds enter cells and (2) if the mutations caused by the moderately soluble chromates differ from those caused by the less carcinogenic soluble and insoluble chromates. Understanding the mode of action of these chromates will provide a foundation for human risk assessment.